Introduction to Clinical Trials
Jan B. Vermorken, MD, PhDDepartment of Medical Oncology
Antwerp University HospitalEdegem, Belgium
ESO student course, Ioannina, 2010
Outline
• Cancer treatment today• Drug development• The bridge to the clinic• Phase I and II trials• WHO vs RECIST criteria• Phase III trials for efficacy• Ethical aspects• Studies with non-cytotoxics• Conclusions
Cancer Treatment Today
• Surgery
• Radiation therapy
• Systemic treatment: – Cytotoxic chemotherapy– Hormone therapy– Immunotherapy– “Targeted therapy”
Long Term Survival (%)
1970 2008• Leukemia in children 0 80• Leukemia in adults 0 45• Bone cancer 5 60• Testicular cancer 0 80• Breast cancer 40 85• Non-small cell lung cancer 0 15• Colon cancer 30 60• Hodgkin’s disease 10 85
From Lab….. To Clinical Trials…. To Standard Practice
Laboratory data Effective Therapy
Drug Development
• Identification of new agents• Preclinical requirements:
efficacy, toxicology (ICH)• Formulation, manufacturing• Regulatory (government) review
(IND submission)• Phase I, II, III clinical trials• Regulatory (government) review
(NDS = new drug submission)
Anticancer Drug Discovery
• Mechanism-based– Rational synthesis or discovery of agents
targeting mechanisms of malignant behavior. Then test in lab models
• Screening/Compound-based– Screen new chemical entities for activity in
cancer models in the laboratory.
Then discover mechanisms of action.
Screening/CompoundBased Discovery
• Majority of available anticancer drugs have been identified by screening
• Sources: plants (vincas, taxanes)microbes (doxorubicin)chemicals (cisplatin)
• Most act by interfering with molecular process of cell division, thus many normal tissues affected.
Preclinical Requirements
A new drug must have the following completed prior to patient testing:
• Demonstrated efficacy in tumor models• Toxicology: 2 species (rodent and non-rodent)• Formulation and manufacturing• Animal pharmacokinetics; mechanism of action
studies
Preclinical Evaluation of Cytotoxic Agents
IN VITROIN VITRO IN VIVOIN VIVO
Mechanism of actionMechanism of action Stage IStage I Stage IIStage II
Target level Maximum tolerated dose Spectrum of activity
Cellular level Dose-limiting toxicities Schedule dependency
Efficacy Route of administration
Cross resistance
Combination therapies
Human Tumor in Nude Mouse
Moving a New Therapy from the Lab to the Clinic
ClinicalClinicalEvaluationEvaluation
LaboratoryLaboratoryExperimentsExperiments
River of UnknownsRiver of Unknowns
Clinical Trials
• Phase I
• Phase II
• Phase III
Phase I Design:Selection of Starting Dose
• Based on mouse toxicity:– 0.1 Mouse Equivalent LD10 (MELD10)
• In instances where dog toxicity show this dose to be toxic, 1/3 Toxic Dose Low (TDL) in dogs is selected as starting dose
Phase I Trials
• Find highest safe dose (1 level below MTD)• Identify side effects
3 pts
3 pts
3 pts
3 pts
3 pts
3 pts
Dose
Severe toxicity
Recommended dose
Dose escalating by modified Fibonacci
Modified Fibonacci Escalation
Dose Level Theory Example
starting Dose x 1
level 2 2 x level 1 2
level 3 1.67 x level 2 3.3
level 4 1.5 x level 3 5
level 5 1.4 x level 4 6.7
level 6 1.33 x level 5 8.8
level 7 1.33 x level n-1 -
Phase II Trials
• Screen drug for activity in cancer patients
• Use recommended dose
• Test it in 15-30 patients with same tumor type
• Look for objective tumor shrinkage: Partial or Complete Response
Adapted from World Health Organization, 1980.
Complete Response: WHO
PrimaryPrimaryTumorTumor
NodesNodes
MetastasesMetastases
Disappearance of all clinical,Disappearance of all clinical,radiologic and biologicradiologic and biologic
signs of tumorsigns of tumor
TreatmentTreatment
TreatmentTreatment
Decrease of the multiple of twoDecrease of the multiple of twotumor diameters by at least 50%tumor diameters by at least 50%
Partial Response: WHO
Adapted from World Health Organization, 1980.
Increase of the multiple of twoIncrease of the multiple of twotumor diameters by at least 25%tumor diameters by at least 25%
Progression: WHO
Adapted from World Health Organization, 1980.
TreatmentTreatment
Example CalculationBaseline Week 8 Week 16 Week 24
Lesion 1234
3.2 x 42.7 x 23.5 x 52 x 2.1
1.5 x 21.3 x 1
2.8 x 2.91 x 1.7
1 x 1.21 x 1
2.5 x 2.8 x 1.1
1.6 x 1.21.2 x 1.32.9 x 2.71.2 x 1.3
Sum Products
39.9( PR < 19.9)
14.1 (PR) 8.1 (PR) 12.9 (PD)
PD calculated from lowest sum on study
RResponse esponse EEvaluation valuation CCriteria riteria iin n SSolid olid TTumors umors (RECIST)(RECIST)
Therasse et al JNCI 2000Therasse et al JNCI 2000
• Intended for use in clinical trials with primary endpoint of objective response
• Measurable lesion >= 20 mm (10 if spiral CT)• Unidimensional assessment: Tumor burden assessed by
summing longest diameters of all measurable lesions up to 10 (5 per organ)
• Four categories of response: CR*, PR*, SD, PD• RECIST widely adopted by cooperative groups, industry,
academia
* Required confirmation
RECIST Guidelines:Response Criteria
• Target lesions ( LD / LD baseline)– CR– PR: 30% (50% surf. area and 65% volume)– SD– PD: 20% (44% surf. area and 73% volume)
• Non-target lesions– CR (including markers)– Non-CR– PD
Example Calculation
Baseline Week 8 Week 16 Week 24
Lesion 1234
3.2 x 4 2.7 x 2 3.5 x 5 2 x 2.1
1.5 x 2 1.3 x 1
2.8 x 2.9 1 x 1.7
1 x 1.2 1 x 1
2.5 x 2 .8 x 1.1
1.6 x 1.2 1.2 x 1.3 2.9 x 2.7 1.2 x 1.3
Sum Products
39.9( PR < 19.9)
14.1 (PR) 8.1 (PR) 12.9 (PD)
Sum Longest Diameter
13.8(PR < 9.7)
7.9 (PR) 5.8 (PR) 7.1 (PD)
PD calculated from lowest sum on study
Unidimensional vs. WHO Criteria: Response Rates in 4,613 Patients from 14 Studies/Data Sets
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12 13 14 total
WHO New
New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guidelines
(verion 1.1)
E.A. Eisenhauer, et al.
European Journal of Cancer 2009; 45: 228-247
What What HAS NOTHAS NOT changed in RECIST 1.1 changed in RECIST 1.1
• Measurable lesions defined by unidimensional measurement
• Tumor burden based on sum of diameters• Categories of response:
– CR– PR (30% decrease in sum from baseline)– SD– PD (20% increase in sum from nadir)
Courtesy of E.A. Eisenhauer
For example: Response classification same…For example: Response classification same…
Time point Response: Patients with Target (+/- non-target) Disease:
Target lesions Non-Target lesions New Lesions Overall response
CR CR No CR
CR Non-CR/Non-PD No PR
CR Not evaluated No PR
PR Non-PD or not all evaluated No PR
SD Non-PD or not all evaluated No SD
Not all evaluated Non-PD No NE
PD Any Any PD
Any PD Any PD
Any Any Yes PD
Summary:Summary:What What HASHAS changed in RECIST 1.1 changed in RECIST 1.1
RECIST 1.0 RECIST 1.1
Measuring tumor burden
10 targets5 per organ
For response: 5 targets(2 per organ)
Lymph node Measure long axis as for other lesions. Silent on normal size
Measure short axis. Define normal size.
Progression definition 20% increase in sum 20% increase and at least 5 mm absolute increase
Non-measurable disease PD
“must be unequivocal” Expanded definition to convey impact on overall burden of disease. Examples.
Confirmation required Required when response primary endpoint—but not PFS
New lesions -- New section which includes comment on FDG PET interpretation
New Lesions (1)New Lesions (1)
• Must be unequivocal: not attributable to different scanning technique or non tumor (e.g. “new” bone lesions may be flare)
• When in doubt continue treatment, repeat evaluation
• If scan showing new lesion is of anatomical region which was not included in baseline scans, it is still PD
Courtesy of E.A. Eisenhauer
New Lesions (2)New Lesions (2)
• FDG-PET: sometimes used by investigators to complement CT. If so:
– Negative FDG-PET at baseline and a positive FDG-PET at follow-up means PD
– No FDG-PET at baseline and a positive FDG-PET at follow up: • It is PD if it corresponds to a new site of disease on
CT• It is equivocal if no new site of disease on CT.
Repeat CT to see if new site apparent next scan: if so, PD date will be that of the initial abnormal FDG-PET scan
• It is not PD if corresponds to a pre-existing site of disease on CT that is not progressing on the anatomic images
What is Efficacy?
• Response Efficacy
• Efficacy is improved:– Cure rates– Survival – Quality of life: i.e. meaningful symptom palliation
• “Response” is a measure of biologic effect which may be a marker for efficacy
Phase III Trials
Once a new agent has shown activity in phase II, comparative trials are usually designed.
New agent can be given alone or in combination
• Objectives: Compare “new” to “standard”
• Endpoints: Survival, toxicity, quality of life.
• Sample Size: 200-2000 patients
Phase III Trials: Definitive Tests of Efficacy
• Large studies to detect “significant” differences in outcomes of interest: – Cure, survival, quality of life
• Randomized design: – Allows unbiased assessment of treatment effect
• Sample Size: – Determines power with which one can detect
postulated differences
How Much Improvement in Efficacy?
• Critical question which drives:– Trial design and sample size– Eventual change in practice
• Patients and physicians (staff) differ on degree of improvement which must be seen to choose a more toxic therapy.
• If patients views are accepted: many trials are too small (underpowered).
Survival Advantage at 3 years Required by Patients vs Staff to Accept Toxic Treatment
02468
1012
<0 1 3 5 10 20 30 40 >50
Patients Staff
% Survival Advantage Threshold
Nu
mb
er
of s
ub
ject
s
From Brundage et al, 1997
Acceptance Thresholds: By 50% or More of Staff
months
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Studies with non-Cytotoxics
“Targeted therapy”
Non-Cytotoxics (“Targeted Therapy”)
General term to describe agents which do not directly target DNA.
Includes agents having targets which are: Cellular
Growth factors and their receptors Signaling pathways
Extracellular Matrix Vasculature
Moving a New Therapy from the Lab to the Clinic
ClinicalClinicalEvaluationEvaluation
LaboratoryLaboratoryExperimentsExperiments
River of UnknownsRiver of Unknowns
Differences between cytotoxic and non-cytotoxic agents
Preclinical Data: Cytotoxic Agent
Dose
Eff
ec
t
-- anti-tumor
toxicity --
Antitumor Effect: Tumor Regression
Time
tum
or
Siz
e control
increasing doses new agent
The Bridge to the Clinicfor Traditional Cytotoxics
• Dose-Toxicity and Dose-Effect relationships: often parallel
• Cause regression of established tumors
• Traditionally:
– phase I trials: endpoint is toxicity
– phase II trials: endpoint is response
• These have allowed dose determination and selection of many agents found in randomized trials to be effectiveeffective i.e. prolong survival
Preclinical Data: Non- Cytotoxic
Effe
cttarget-
toxicity-
- antitumor
Effe
ct
target-
toxicity-
- antitumor
Antitumor Effect: Growth DelayTu
mor
Siz
e control
increasing doses new agent
The Bridge to the ClinicFor Novel Non-Cytotoxics
• Dose-Toxicity and Dose-Effect relationships: may not be parallelmay not be parallel
• May notMay not cause regression of established tumors
• Thus, for newer agents:
– phase I trials: endpoint is uncertain
– phase II trials: endpoint is uncertain
Ethical Committee: Roles and Function
• To safeguard the rights, safety and well-being of trial subjects
• Documented procedures
• At study start assess:– Scientific justification for proposed research and use of human
subjects– Weigh potential benefits/risks– Consent document and process– Qualifications of investigator and team
• Ongoing review
Summary
• Journey from the laboratory to clinical practice requires several steps
• Promising new therapies must undergo evaluation in patients:– Phase I: find dose, side effects– Phase II: look for hints of activity– Phase III: definitive tests of efficacy
• All trials must have ethical committee review and patient consent
Declaration of Helsinki: Sample Statements
• It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject
• Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation
• Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected
• The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol
Ethics and Consent
• History:
– War Crimes– Tuskagee syphilis study– Jewish Chronic Hospital study– Willowbrook study
Complex signalling pathways in oncology
Hanahan D, Weinberg RA. Cell 2000;100:57–70
DR4, DR5
Difficult to target
Src
IGF-II, HGF, Ang2
Growth factor receptors
Growth factorreceptor ligands
51v3
EGFR, ErbB2, VEGFR-2,IGF-1R, MET, KIT, RET, Tie2
RResponse esponse EEvaluation valuation CCriteria riteria IIn n SSolid olid TTumours umours
RECIST guidelinesRECIST guidelines
Wilhelm S, et al. Clin Cancer Res 2004;64:7099–109
Sorafenib: targets both tumour cell and vascular compartments
Tumour cell Endothelial cell or pericyte (vascular)
Angiogenesis:differentiationproliferationmigrationtubule formation
Raf
VEGFR-2PDGFR-
MEK
Apoptosis
Proliferation
PDGF
VEGF
Survival
Ras
Nucleus
Ras
ERK
Raf
MEK
Apoptosis
ERK
PDGF VEGFParacrine stimulation
Sorafenib
KIT/Flt-3/RET
Mitochondria
MitochondriaMcl-1
HIF
Sorafenib
Sorafenib
Sorafenib
Nucleus
HIF = hypoxia inducible factor; VEGF = vascular endothelial growth factor VEGFR = VEGF receptor; PDGF = platelet-derived growth factor PDGFR = PDGF receptor; Mcl-1 = myeloid cell leukaemia-1
• A multi-kinase inhibitor of– serine/threonine kinases: C-Raf (Raf-1) and B-Raf-1– receptor tyrosine kinases: VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, and c-KIT
Codes of Conduct: International Standards
• Nuremberg Code• Declaration of Helsinki• Good Clinical Practice
• Adopted by most nations
Elements of Informed Consent
• Purpose of the trial and that it involves research
• Treatment and how it is assigned. Number of subjects planned
• Duration of study and procedures involve
• Experimental aspects
• Possible benefits and likely risks
• Voluntary nature
• Alternative treatment
• Access to data and confidentiality
Summary (2)
• Some drugs showing activity in animal studies or phase II turn out to be inactive in phase III
• New agents are now exploiting the scientific discoveries of the last decades:– Targeting differences between cancer and normal cells– Targeting blood vessels that support cancer growth
• Many such new agents now being investigated in clinical trials in several areas of the world
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